Methamphetamine abuse is a significant public-health concern and is the primary form of amphetamine abused in the United States. Between 1996 and 2002, the number of Americans that reported using methamphetamine increased by 250%. Amphetamine admissions to treatment program increased by nearly 500% between 1992 and 2002. Methamphetamine use made up 90% of all amphetamine treatment admissions. Because of the public-health concerns, identifying an effective pharmacotherapy for the management of methamphetamine dependence is imperative. Methamphetamine is thought to exert its. behavioral effects by promoting the release of several monoamines, including dopamine (DA), serotonin (5- HT) and norepinephrine (NE), which has prompted some theoreticians to suggest targeting multiple systems for the development of a pharmacotherapy. Partial agonists at these neurotransmitter systems may represent a novel and effective means to treat stimulant dependence. In support of this notion, partial agonists at D2 and 5-HT1A receptors attenuate many of the behavioral effects of amphetamines in laboratory animals In the present application, we propose a series of experiments to determine the efficacy of iripiprazole, an atypical antipsychotic that is a D2 and 5-HT1A partial agonist and a 5-HT2A antagonist, as a putative pharmacotherapy for methamphetamine dependence. The results of a recent experiment conducted in our laboratory suggest that aripiprazole significantly attenuates the discriminative-stimulus and some of the positive subjective effects of d-amphetamine in humans. The present project has three specific aims. The first specific aim is to characterize the behavioral pharmacology of methamphetamine in humans. The second specific aim is to assess the safety and tolerability of methamphetamine in combination with aripiprazole. The third specific aim is to determine the efficacy of aripiprazole as a putative pharmacotherapy, by examining the discriminative-stimulus, reinforcing, and subjective effects of methamphetamine in humans following chronic pretreatment with aripiprazole. The proposed research will provide initial scientific and clinical information regarding the use of aripiprazole as a pharmacotherapy for the treatment of methamphetamine dependence, and guide the design of future clinical trials.